a. Field of the Invention
This invention relates to nonapeptides of formula 1 EQU (pyro)-Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHR (1)
in which R is lower alkyl, and intermediates for the synthesis thereof.
The nonapeptides of this invention also are called L-pyroglutamyl-L-histidyl-L-tryptophyl-D-seryl-L-tyrosyl-D-leucyl-L-leucyl -L-arginyl-L-prolyl lower alkylamides, and may be designated by the abbreviation [D-Ser.sup.4,D-Leu.sup.6,desGly-NH.sub.2.sup.10 ]-LH-RH (lower alkyl)amides.
B. Background of the Invention
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are both gonadotrophic hormones elaborated by the pituitary gland of humans and of mammals. LH together with FSH stimulates the release of estrogens from the maturing follicles in the ovary and induces the process of ovulation in the female. In the male, LH stimulates the interstitial cells and is for that reason also called interstitial cell stimulating hormone (ICSH). FSH induces maturation of the follicles in the ovary and together with LH, plays an important role in the cyclic phenomena in the female. FSH promotes the development of germinal cells in the testes of the male. Both LH and FSH are released from the pituitary gland by the action of LH- and FSH-releasing hormone, and there is good evidence that said releasing hormone is elaborated in the hypothalamus and reaches the pituitary gland by a neurohumoral pathway, see e.g., A.V. Schally, et al., Recent Progress in Hormone Research, 24, 497 (1968).
The natural LH- and FSH-releasing hormone has been isolated from pig hypothalami and its constitution elucidated by A. V. Schally, et al., Biochem. Biophys. Res. Commun., 43, 393 and 1334 (1971), who proposed the decapeptide structure EQU (pyro)-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2.
this constitution has been confirmed by synthesis; for example, see H. Matsuo, et al., Biochem. Biophys. Res. Comm., 45, 822 (1971) and R. Geiger, et al., ibid, 45, 767 (1971).
Hereinafter the natural LH- and FSH-releasing hormone is called LH-RH.
Because of the importance of LH-RH to both diagnostic and therapeutic medicine, considerable interest has been shown in the preparation of new compounds having improved properties over the natural hormone. One approach to this goal has been the selective modification or replacement of amino acid residues of LH-RH with other amino acids. Although in a few instances peptides containing such alterations have been found to be more active than LH-RH, for example, [D-Ala.sup.6 ]-LH-RH, A. Arimura, et al., Endocrinology, 95, 1174 (1974),]D-Leu.sup.6 ]-LH-RH and [D-Leu.sup.6, desGly-NH.sub.2.sup.10 ]-LH-RH ethylamide, J.A. Vilchez-Martinez, et al., Biochem. Biophys. Res. Commun., 59, 1226 (1974), for the most part the modified peptides have been less active.
Now it has been found that the replacement of the L-seryl moiety in position 4 of LH-RH with the D-seryl moiety, replacement of the glycyl moiety in position 6 by a D-leucyl moiety, and replacement of the glycinamide moiety in position 10 by a lower alkyl amide group gives a nonapeptide that is much more active and longer acting than LH-RH.
The present finding that a change in the asymmetry of the seryl residue in position 4 in conjunction with the introduction of a D-leucyl residue position 6 results in enhanced activity and longer duration of action for the nonapeptides of this invention is quite suprising, especially in view of the fact that with respect to LH-RH changes in the asymmetry of its amino acid residues and/or replacement thereof generally lead to a derivative which is far less active than LH-RH itself; for instance see Y. Hirotsu, Biochem. Biophys. Res. Commun., 59, 277 (1974). Further in keeping with this thought is our finding that [D-Ser.sup.4 ]-LH-RH has less than 5% of the LH-RH activity of the natural hormone.
The attributes of the present nonapeptides have practical significance: the lesser minimum effective dose reducing side effects as well as the cost for the preparation of the compound and the longer acting property reducing the need for frequent administration.